Diflorasone diacetate, fluocortolone, fluocinolone acetonide, fluocinonide, paramethasone and fluprednisolone are 6.alpha.-fluoro-.DELTA..sup.1,4 -3-keto steroids which are of pharmacological value primarily as topical anti-inflammatory agents.
Present technology requires that the production of these 6.alpha.-fluoro-.DELTA..sup.1,4 -3-keto steroids necessitates the epimerization of the 6.beta.-fluoro group of a steroid prior to .DELTA..sup.1 -dehydrogenation. See, for example, U.S. Pat. Nos. 3,980,778, 3,014,938 and 3,126,375 and J. Am. Chem. Soc. 82, 4001 (1960).
It would be highly desirable to be able to epimerize a fluorine atom at the 6.beta.-position in a .DELTA..sup.1,4 -3 keto steroid. However, prior to the present invention there was no known procedure for accomplishing this process.
Others have reported that they have attempted to do this but were unsuccessful. For example, D. H. R. Barton et al. reported in Nouveau Journal De Chimie 1, 315 (1977) an unsuccessful attempt to epimerize a flourine atom at the 6.beta.-position in a .DELTA..sup.1,4 -3-keto steroid. Barton tried epimerization of a 6.beta.-fluoro-.DELTA..sup.1,4 -3-keto steroid by use of triphenylmethyl lithium. Instead of obtaining epimerization he obtained elimination of the fluorine atom. The present invention overcomes this problem.
H. J. Ringold and S. K. Malhotra in Tetrahedron Letters 669 (1972) reported deconjugation of a .DELTA..sup.4 -3-keto steroid. However, the authors reported they were unable to deconjugate a .DELTA..sup.1,4 -3-keto steroid, see page 672.
E. L. Shapiro et al. in Steroids 3, 183 (1964) reported deconjugation of a .DELTA..sup.1,4 -3-keto steroid to give a .DELTA..sup.1,5 -3-keto steroid. However, the reactant did not contain a fluorine atom at C-6. Barton, supra, reported an attempt to deconjugate a 6.beta.-fluoro-.DELTA..sup.1,4 -3-keto steroid. He reported that instead of obtaining deconjugation he obtained elimination. The present invention has solved this problem and permits deconjugation of 6.beta.-fluoro-.DELTA..sup.1,4 -3-keto steroids.
U.S. Pat. No. 4,188,322 claims a process for introduction of a fluorine atom in the 6.alpha.-position of a 9.beta.,11.beta.-epoxy-.DELTA..sup.1,4 -3-keto steroid by first forming the corresponding 3-enol derivative by acylation or etherification followed by reaction with a suitable halogenating agent.
Great Britain Pat. No. 2,018,258 discloses virtually the same process as does U.S. Pat. No. 4,188,322.
Both U.S. Pat. No. 4,188,322 and Great Britain Pat. No. 2,018,258 differ from the process of the present invention in that these processes introduce a fluorine atom into the steroid at the C.sub.6 position directly in the .alpha. configuration while the process of the present invention introduces a fluorine atom at the C.sub.6 position in the opposite or .beta. configuration followed by epimerization to the .alpha. position. In addition, the process of the present invention advantageously does not require that the C.sub.3 keto group be protected as an enol ether or ester.
Polish Pat. No. 85,557 discloses a process for isomerization of a 6.beta.-fluoro-.DELTA..sup.1,4 -3-keto-11-oxygenated steroid to the corresponding 6.alpha.-fluoro-.DELTA..sup.1,4 -3-keto-11-oxygenated steroid by use of isomerizing agents which are acids. In the process of the present invention the transformation of the 6.beta.-fluoro-.DELTA..sup.1,4 -3-keto steroid (IV) to the corresponding 6.alpha.-fluoro-.DELTA..sup.1,4 -3-keto steroid is accomplished by a basic agent not an acidic one. In addition, the process of the present invention does not require an 11-oxygenated steroid.